The ability to control expression of particular polynucleotides upon gene transfer is a useful function, particularly for applications where specific localized activity is desired. Such is the case for cancer, where it is prudent to confine destructive or lethal gene products to the cancerous cells while preventing at least in part such activity in normal cells.
Breast Cancer Tissue-Specific Expression
Current breast cancer therapies, such as chemotherapy (CT) and radiotherapy, have low selectivity for tumor cells and side effects for normal tissues. To minimize the side effects, these therapies are generally given in an intermittent manner, allowing normal cells to recover between treatment cycles. However, during the recovery period, some surviving cancer cells become more resistant to the treatment because of gene mutation. Consequently, cancer recurrence or progression may occur. Tumor-targeting gene therapy minimizes treatment side effects and the risk of developing resistance by acting on the tumor-specific signaling pathways.
One breast cancer-specific promoter described herein comprises selected portions of the topoisomerase IIα gene. Although the 5′ flanking region of the topoisomerase IIα gene has been known for some time Hochhauser et al., 1992), a particular active region described herein has not been demonstrated to be useful for breast cancer tissue, even when linked to cytomegalovirus enhancer (Mo et al., 1998).
Another breast cancer-specific promoter described herein comprises selected portions of the transferrin receptor promoter. Transferrin receptor expression has been localized in breast tissue (Fuernkranz et al., 1991; Shterman et al., 1991) and in breast cancer (Bauman et al., 1997; Shindelman et al., 1981), but a particular region that provides such activity has not been disclosed.
Prostate Cancer Tissue-Specific Expression
Prostate-specific promoters, such as PSA, probasin, and hK2, have been recently developed. The activities of these promoters are androgen-dependent and the use of androgen-responsive vectors to direct expression of therapeutic genes to prostatic tissue is helpful for numerous disease stages. Although such prostate-specific promoters responsive to androgen receptor have been developed by the present inventors (Xie et al., Cancer Res 2001) and other groups (Zhang et al., Mol Endocrinol 2000), these androgen-dependent promoters may be less active after castration or androgen ablation therapy, which are the main modalities for progressive prostate cancer treatment. Patients treated with compositions comprising these promoters may fail this kind of therapy and die of recurrent androgen-independent prostate cancer (AIPC). A novel promoter for prostate cancer gene therapy that will be active in both ADPC and AIPC to treat metastatic and recurrent hormonal refractory prostate cancer is lacking in the art.
Pancreatic Cancer Tissue-Specific Expression
Pancreatic cancer is one of the most aggressive human malignancies and the fifth cause of cancer death, given that no effective modalities are available. The present invention addresses such a need by providing a promoter effective to regulate expression of a therapeutic polynucleotide specifically in pancreatic cancer cells.